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Background: SARS-CoV-2 infection is accompanied by acute olfactory disturbance in as high as 70% of cases. This loss is associated with decreased olfactory bulb volume. As time passes, the anosmia tends to subside, but the OB volume decrease does not. Volume reductions in primary and secondary olfactory cortex are also seen following SARS-CoV-2 infection. Nevertheless, concurrent SARS-CoV-2 infection effects on olfactory discrimination, olfactory bulb volume, primary olfactory cortex and its targets have not been investigated. To explore this possibility, we measured olfactory discrimination, olfactory bulb volume, primary olfactory cortex and basal ganglia volume in patients who had SARS-CoV-2 infection more than 12 weeks previously, who were then divided into COVID and long-COVID groups on the basis of selfreported fatigue and concentration complaints. Method(s): This cross-sectional study included 25 post-infection and 19 demographically-matched, no-COVID control participants, we investigated effects on olfaction using NIH Toolbox Odor Identification Test and the Monell Smell Questionnaire. GM structure was assessed with voxel-based morphometry and manual delineation of high resolution (1mm3), T1- and T2-weighted MRI data. Linear regression was used to model group effects on GM structure, adjusting for age, sex, education and total intracranial volume. CAT12/SPM12 and R were used for image processing and statistical modeling. Result(s): Results. The NIH Toolbox Odor Identification Test failed to show differences among the groups. In contrast, the Monell Smell Questionnaire revealed persistently diminished and distorted smell in 50% of the long-COVID sample. Olfactory bulb volume was lower in the long-COVID group (p=0.02). Primary olfactory cortex volume was reduced in the long-COVID group (p=0.004). Caudate volume was also lower in the long-COVID group (p=0.04). Conclusion(s): Conclusions. In the absence of olfactory discrimination problems, long-COVID, but not COVID, patients experience persistent olfactory loss and distortion. These perceptual problems are associated with lower olfactory bulb, primary olfactory cortex, and caudate volume, suggesting that the effects of SARS-CoV-2 infection can extend beyond the olfactory periphery in some cases to affect central targets. (Figure Presented).
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Background: Previous longitudinal studies (n=6) of objective olfaction performance post-acute COVID-19 have a maximum follow-up of 6-month and do not often test biomarkers. Although olfactory dysfunction appears to improve within two months of symptom onset, 4/6 longitudinal studies show persistent olfactory impairment. Method(s): PCR-confirmed COVID-19 patients in the prospective ADAPT cohort (Sydney, Australia) were assessed across 18 acute symptoms and hospitalization status: 40% mild, 50% moderate, 10% severe/hospitalised - none deceased). Blood samples were taken 2 (N=179), 4 (N=148) and 12-month (N=118) post-diagnosis. The NIH Odor Identification Test (OIT) and the Cogstate brief cognitive battery were performed. 58 also had an olfaction test at 24-month. The OIT raw data were transformed into demographically-corrected T-scores. OIT's attrition was completely random and only initial age (40+/-15 versus 47+/-15) differed between patients lost to follow-up and those in the study at 24-month. We tested peripheral neurobiomarkers (NFL, GFAP, S100B, GM-CSF) and immune markers (Interleukin-IL panel: 1-beta, 1Ralpha, 4, 5, 6, 8, 10, 12p40, 12p70, 13, and MCP-1, TNF-alpha and INF-gamma), analyzed as Log transformed and elevated/normal range using published references. Our previous analyses had shown no relationship with the kynurenine pathway, but an association of impaired olfaction and impaired cognition at 2-month only. Linear mixed effect regressions with time effect (months) tested olfaction trajectories (random subject effect) and their association with the biomarkers (main and time interaction). Result(s): At 2 months post-diagnosis 30% had impaired olfaction and those who had acute severe disease were more likely to be impaired (54% versus 26%, p=.009). 21%, 31% and 37% had impaired olfaction at 4, 12 and 24-months. Olfactory performance declined over time (p< .0001), which was dependent on the initial performance (Fig 1). Neurobiomarkers were within the normal range. IFN-gamma, IL-1Ralpha, IL-13 and TNF-alpha increased across time, p< .03-p< .0005. TNF-alpha and IFN-gamma showed a time covariance with poorer olfaction performance. Conclusion(s): Post-acute mild to moderate COVID-19 is associated with a declining olfactory performance up to 2-yr post-diagnosis, especially when initially impaired with the provisio of attrition although random. Olfactory performance decline may be mediated by upregulated immune parameters which are distinct from those driving cognitive changes. (Figure Presented).
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Background: Olfactory dysfunction (OD) is a common symptom of Corona Virus Disease 2019 (COVID-19). It is defined as the reduced or distorted ability to smell during sniffing (orthonasal olfaction) and represents one of the early symptoms in the clinical course of COVID-19 infection. A large online questionnaire-based survey has shown that some post-COVID-19 patients had no improvement 1 month after discharge from the hospital. Objective: To explore the efficacy of acupuncture for OD in COVID-19 infected patients and to determine whether acupuncture could have benefits over sham acupuncture for OD in post-COVID-19 patients. Methods: This is a single-blind, randomized controlled, cross-over trial. We plan to recruit 40 post-COVID-19 patients with smell loss or smell distortions lasting for more than 1 month. Qualified patients will be randomly allocated to the intervention group (real acupuncture) or the control group (sham acupuncture) at a 1:1 ratio. Each patient will receive 8 sessions of treatment over 4 weeks (Cycle 1) and a 2-week follow-up. After the follow-up, the control group will be subjected to real acupuncture for another 4 weeks (Cycle 2), and the real acupuncture group will undergo the 4-week sham acupuncture. The primary outcomes will be the score changes on the questionnaire of olfactory functioning and olfaction-related quality of life at week 6, 8, 12, and 14 from the baseline. The secondary outcomes will be the changes in the olfactory test score at week 6 and 12 from the baseline measured by using the Traditional Chinese version of the University of Pennsylvania Smell Identification Test (UPSIT-TC). Discussion: The results of this trial will help to determine the effectiveness of acupuncture for OD in post-COVID-19 patients. This may provide a new treatment option for patients.
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Introduction: Olfactory dysfunction (OD) is a prevalent and characteristic symptom among individuals with COVID-19 infection. Although most patients with COVID-19-related OD experience a significant recovery, there exists a substantial population of patients with persistent OD with limited therapeutic options. Method(s): Patients with laboratory-confirmed or clinically suspected COVID-19 infection and self-reported new onset OD from March 2020 to October 2021 were prospectively recruited for a randomized, placebo-controlled, doubleblinded clinical trial. Patients with evidence of quantitative OD, defined as a Brief Smell Identification Test (BSIT) score of 9 or less, were eligible for study inclusion. The experimental group received 2 g of omega-3 fatty acid (O3FA) supplementation, including 1366-mg eicosapentaenoic acid and 504-mg docosahexaenoic acid, while the control group received an identical placebo, each to be taken daily for 6 weeks. The primary outcome was change in BSIT score from initial test to a 6-week follow-up BSIT. Result(s): A total of 117 patients were included in analysis, including 57 patients in the O3FA group and 60 in the placebo group. The mean duration of OD prior to study enrollment was 200.1 days with no significant difference between groups (P=.685). Patients receiving O3FA supplementation demonstrated a mean BSIT improvement of 1.12+/-1.99 compared with 0.68+/-0.86 in the placebo group (P=.385). Among those with severe hyposmia, defined as a BSIT score of 7 or less, patients in the O3FA group (n=23) demonstrated a BSIT improvement of 2.30+/-0.77 compared with 1.63+/-1.82 among those in the placebo group (n=16, P=.255). Conclusion(s): Our study showed a trend toward improved olfactory recovery among COVID-19-related OD patients receiving high doses of O3FA supplementation at a 6-week follow-up time point. Future work will be needed to better define the effectiveness and durability of O3FA supplementation as a treatment for COVID-19-related OD.
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Introduction: Olfactory dysfunction (OD) affects more than 3 million US adults. The number of patients with post viral olfactory dysfunction (PVOD) is expected to increase secondary to the worldwide COVID-19 pandemic. Preliminary studies have demonstrated the efficacy of platelet-rich plasma (PRP) in restoration of smell in both animals and humans. To date, human studies have utilized injectable PRP only. We describe our pilot study investigating the use of topical PRP as a novel delivery method for smell restoration and contribute to existing literature demonstrating the promise of PRP as a therapeutic. Method(s): Pilot study from September 2020 to January 2022. Patients >18 years with hyposmia diagnosed via Brief Smell Identification Test (B-SIT) score <8 were included. PRPimpregnated Surgifoam was placed into bilateral olfactory clefts monthly for at least 3 months. Patients completed the B-SIT at baseline and 1 month after each treatment. Result(s): Eight patients underwent at least 3 treatments and completed the B-SIT at month 4. Average age was 56.3 years;mean smell loss duration was 19.3 months. Etiologies included PVOD, post-COVID (5), and idiopathic. Mean change in B-SIT after 3 treatments was +1.06. Of patients, 62.5% had achieved the minimal clinically significant difference of >1 on B-SIT after treatments 2 and 3. Patients with smell loss <12 months demonstrated greater B-SIT scores at 4 months (+1.6 vs +0.2). Two patients achieved B-SIT >8 after 3 treatments. Of patients who have returned thus far for a fourth treatment, 1 additional patient scored >8. Conclusion(s): We present the largest pilot study to date for the use of PRP in treatment of OD and the first study to develop methods for topical delivery in human subjects. Topical PRP may serve as a less invasive, efficacious therapy for patients. Further, randomized control trials are warranted to investigate the required number of topical PRP treatments for smell restoration.
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Introduction: Almost 30% of olfactory dysfunction (OD) arises after a viral infection with increased incidence due to COVID-19. Hypothesized SARS-CoV-2 viral attachment to the olfactory epithelium differs from the traditional postviral OD (PVOD) mechanism. Hence, manifestations of OD may differ between the two etiologies. This study evaluates the difference in smell perception between post-COVID-19 OD and postviral or idiopathic etiologies. Method(s): This observational study, approved by the institutional review board, was conducted between September 2020 and January 2022 in adult patients with more than 6 months nontraumatic OD with no perceived improvement in smell even after 3 months of conservative treatment. OD in these patients was categorized as COVID-19 or non-COVID-19 related. Demographics, duration of OD, and Brief Smell Identification Test (B-SIT) scores were analyzed. Continuous variables were compared by t test, while categorical variables were compared by chi2 test using SPSS 27 (IBM Corp). Result(s): Of the 26 patients included in the study, 42.3% reported persistent OD following COVID-19 infection, while 57.7% had non-COVID-19-related OD. The mean B-SIT score in post-COVID-19 OD was 6.81+/-2.15 compared with 3.87+/-2.2 in the non-COVID-19 OD group, with the difference being statistically significant at 3.40 (P=.001). While race and gender ratios were similar between the groups, age (42 vs 54, P=.048) and duration of loss of smell (10 months vs 49 months, P<.001) had significant differences. Conclusion(s): This study shows that patients suffering from COVID-19-related OD may have normal scores on scratch and sniff smell tests, possibly because of the difference in the affected site of the olfactory pathway. Current hypotheses focus on olfactory epithelial damage in COVID-19 vs neuronal in PVOD. Differences seen in age and duration of smell loss between groups may be secondary to newfound worldwide attention to OD, while patients with OD etiologies predating COVID-19 may have newly sought treatment at this time. Olfactory threshold testing may be required for accurate assessment of post- COVID-19 OD. Larger studies are required to help delineate differences between these olfactory disturbance etiologies.
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Objective: To assess olfactory function in individuals with classical (infratentorial) superficial siderosis (iSS) Background: iSS is a rare but potentially disabling and progressive neurological disorder that commonly involves auditory and vestibular neural pathways. Olfactory nerve function may also be affected but dedicated studies assessing this in iSS are lacking. Design/Methods: Ethics approval was granted. Eleven participants with a known diagnosis of iSS and no prior symptoms or history of COVID-19, were provided with the 40-item (British version) University of Pennsylvania Smell Identification Test (UPSIT) kits by post. The scores (40 as maximum best) were graded as normal, microsmia (mild/moderate/severe) and anosmia, as compared with age- and gender-matched norms;percentile values were obtained. Smoking status was determined;pack-years, years since smoking-cessation and disease duration (from presumed causative event) were calculated. Results: Ten participants completed the test. The mean (±standard deviation, SD) age was 52.5(±14.5) years;2 participants (20%) were females;6 participants (60%) never smoked;1 participant (10%) was a current smoker. The mean(±SD) UPSIT score was 25.5(±7.8), with no difference between males/females (t(10)=-1.528, p=0.165). The mean(±SD) disease duration (n=9) was 23.2(±11.4) years. The UPSIT scores were statistically significantly lower than age-/gender-matched norms (t(9)=4.016;p=0.003), and below the 30th centile for all participants (<10th percentile for 4 (40%);in 10-20th percentile for 5 (50%);in 20-30th percentile for 1 (10%)). Six participants (60%) had anosmia or moderate microsmia and 4 (40%) had mild microsmia. There was no correlation (as assessed by Kendall's tau-b, Tb ) (p>0.05) between the UPSIT scores and: age (Tb (10)=-.114);years since smoking-cessation (Tb (4)=.333), pack-years (Tb (4)=-.333), or disease duration (Tb (9)=.310). Conclusions: We report a novel quantitative assessment of the prevalence of olfactory dysfunction in iSS. Given its high prevalence, olfactory dysfunction may be another key feature of the iSS clinical syndrome that is currently under-investigated but should routinely be assessed. .
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Background: COVID-19 infection-associated cognitive and olfaction impairments have an unclear pathogenesis, possibly related to systemic disease severity, hypoxia, or illness-associated anxiety and depression. A biomarker for these neurocognitive changes is lacking. The kynurenine pathway (KP) is an interferon stimulated myeloid cell mediated tryptophan degradation pathway important in immune tolerance, neurotoxicity and vascular injury, that is dysregulated in COVID-19. We hypothesized that neurocognitive impairments were associated with an activated KP. Methods: The current analysis includes COVID-19 patients as part of the ADAPT study, a prospective cohort (St Vincent's Hospital Sydney, Australia). Disease severity was assessed with 18 acute symptoms and hospitalization status. Blood samples were taken 2 months (N=136) and 4 months (N=121) post diagnosis along with cognitive (Cogstate Computerized Battery, CBB;NIH toolbox Odor Identification Test, OIT) and mental health screenings (DMI-10;IESR, SPHERE-34 Psychological subscale grouped into a composite score). KP metabolites (PIC, QUIN, 3HK, 3HAA, AA, KYN, TRP, log for analyses except for TRP) were measured by GC-MS and uHPLC. The CBB and OIT data were demographically-corrected. CBB follow-up data was also corrected for practice effect. Linear mixed effect regression models with time effect (days post diagnosis) tested whether cognition, and olfaction were associated the KP (main and time interaction);while correcting for disease severity, mental health and comorbidities. Results: 136 patients: mean age=46±15;40% females;90% English speaking background;disease severity: 40% mild, 50% moderate, 10% severe/hospitalised;34% treated comorbidities. At 2 months post diagnosis, 16% had cognitive impairment, and 25% had impaired olfaction. Cognitive impairment was more common in those with anosmia (p=.05). At 4 months, 23% had cognition impairment and 20% had impaired olfaction. QUIN (p=.001), 3HAA (p<.0001) increased over the study period, while TRP decreased (p=.02). QUIN level associated with poorer cognitive scores (p=.0007;QUIN (nM) between 800-1000 was most predictive). There was no time∗QUIN interaction. QUIN association to cognition persisted when severe cases were excluded (p<.005). Conclusion: COVID-19 is associated with KP activation, and the latter with cognitive impairment. QUIN was the only biomarker associated with cognitive impairment, and may be useful in monitoring and elucidating COVID-19 neuropathogenesis and treatment.
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We identified associations between measured olfactory dysfunction (OD) and dietary parameters in a nationally representative sample of US adults. In NHANES 2013-2014, 3,206 adults 40 and over completed a measured smell exam (8-item odor identification test) as well as a 24-hour dietary recall interview administered by trained interviewers. OD was defined as incorrect identification of 3 or more (out of 8) odors;severe OD was defined as incorrect identification of 5 or more odors. Diet quality was assessed using the Healthy Eating Index 2015 (HEI-2015), where higher scores indicate higher diet quality. Other dietary variables included 24-h energy intake, and % energy from fat, added sugar, and alcohol. Survey-weighted multiple linear regression models estimated independent associations between OD and dietary variables. Models were stratified by sex, and adjusted for age, race/ethnicity, education, income, smoking and chronic disease status. The prevalence rates of OD and severe OD were 12.8% (95% CI: 10.8%, 15.2%) and 2.5% (95% CI: 1.9%, 3.5%), respectively;the average HEI-2015 score was 52.9 (0.7 SE). In men, severe OD was associated with lower energy intake with an adjusted mean difference of -403.9 (95% CI: -710.4, -97.3) between those with and without severe OD. In women, severe OD was associated with lower % of energy intake from alcohol with an adjusted mean difference of -1.71 (95% CI: -2.5, -0.95). No significant associations were observed with other dietary variables. These findings are generally consistent with the broader view that disrupted olfactory function often has meaningful dietary implications, a concern with increased public health relevance given the transient and persistent olfactory disruption observed with COVID-19 infections.
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The current COVID-19 pandemic requires the use of safe olfactory testing protocols that can be applied on a large scale. To this end, we developed the Chemosensory Perception Test (CPT), a quick test carried out at home to objectify olfactory and gustatory complaints. Specifically, it assesses orthonasal and retronasal olfaction as well as gustation using common North American household items. This study aims to compare the CPT scores with the participants' initial olfactory complaint and with standardized testing. We hypothesized CPT scores to be significantly lower in participants having a subjective and/or objective olfactory dysfunction (OD). Participants were tested using the CPT and the University of Pennsylvania Smell Identification Test (UPSIT). They were divided in two groups according to initial olfactory complaint or UPSIT score. CPT olfactory scores (average orthonasal and retronasal scores) were compared between groups using t-tests;association between CPT and UPSIT scores was analyzed with Pearson's correlation coefficient. We obtained preliminary results from 26 participants: 15 participants (57.7%) had subjective OD and 14 participants (53.8%) showed objective OD according to UPSIT. Average CPT orthonasal (9.3 vs 6.3;t(17.888)=5.594, p<0.001) and retronasal (9.6 vs 6.1;t(15.842)=3.985, p=0.001) scores were significantly lower in participants who identified themselves as having OD. However, we did not find any significant difference when groups were divided into normosmia/ microsmia according to the UPSIT. Nevertheless, average CPT orthonasal (r=0.461, p=0.018) but not retronasal scores were correlated with UPSIT scores. Our results suggest that the CPT is consistent with subjective and objective OD and can be used in the current context, especially in longitudinal study designs.
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Background: Commercially available smell tests are primarily used in research or in-depth clinical evaluations, but are too costly and lengthy for population surveillance in health emergencies like COVID-19. We developed the SCENTinel 1.0 test which rapidly evaluates three olfactory functions (detection, intensity, and identification). We tested whether self-administering the SCENTinel 1.0 test discriminates between individuals with smell loss or average smell ability (normosmics), and provides comparable performance as the validated and standardized NIH Toolbox® Odor Identification Test in normosmics. Methods: Using Bayesian linear models and prognostic classification algorithms, we compared the SCENTinel 1.0 performance of a group of self-reported anosmics (N=111, 47±13yo, F=71%,) and normosmics (N=154, 47±14yo, F=74%), as well as individuals reporting other smell disorders (e.g., hyposmia, parosmia;N=42, 55±10yo, F=67%). Results: Ninety-four percent of normosmics met our SCENTinel 1.0 accuracy criteria, while only 10% of anosmics and 64% of individuals with other smell disorders did. Overall performance on SCENTinel 1.0 predicted belonging to the normosmic group better than identification or detection alone (vs. anosmic: AUC=0.95, Sensitivity=0.72, Specificity=0.94). Odor intensity provided the best single-feature predictor to classify normosmics. Among normosmics, 92% met the accuracy criteria at both SCENTinel 1.0 and the NIH Toolbox® Odor Identification Test. Conclusions: SCENTinel 1.0 is a practical test able to discriminate individuals with smell loss and is likely to be useful in many clinical situations, including COVID-19 symptom screening.